The primary long-term goal of this project is to understand the neural mechanisms that contribute to the self-administration of opiate and stimulant drugs of abuse. Behavioral pharmacological methodologies will be applied to address three specific aims each of which builds upon and/or extends work conducted during the first fourteen years of this project. These are: 1) To dissociate the underlying motivational processes that serve to initiate drug-seeking behavior, from the reinforcing processes that are activated as a consequence of drug self-administration; 2) To continue and extend investigations of the mechanisms involved in the "relapse" of drug-abuse behavior as modeled in an operant runway test of response-reinstatement; and 3) To continue investigation of the nature and neurobiology of the putative anxiogenic/aversive properties of self-administered cocaine. The primary self-administration methodology employed in this work is a unique operant runway test of IV drug reinforcement. Animals are trained to traverse a straight arm runway once each day for a reward consisting of IV drug reinforcement (i.e., cocaine, heroin, speedball, nomefensine, cocaethylene) delivered upon the Ss' entry into the goal box. In this context, the speed with which the undrugged animal traverses the runway to return to a place where it had previously received the drug reinforcer, provides a valid and highly reliable index of the Ss' motivation to obtain the reinforcer. In addition, because the animals are tested on a single trial per day, the resulting operant data are devoid of nonspecific effects produced by the drug reinforcers themselves. Since motivated states (including those activate drug-seeking behavior) are defined, in part, by the presence of internal activation or arousal, the project has begun the use of small implanted radio-telemetric devices that provide physiological data (heart rate, respiration, ECG, core temperature...) about the internal state of the animal during behavioral testing. The combination of these behavioral and physiological measures will permit the initiation of studies intended to investigate the complex relationship between central and sympathetic nervous systems in the production of motivated behavior. Experiments are planned on the IV and IC self-administration of reinforcing drugs in the runway, on the underlying mechanisms that produce the "activation" of drug-seeking behavior upon presentation of drug-predictive environmental stimuli.